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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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June 29, 2011

Avastin At the FDA Today: Passion Should Lose

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Posted by Derek

Today is Day Two of the FDA's hearings on Avastin for metastatic breast cancer. Note: if you want to follow things in near real time, I'd suggest a Twitter search for #Avastin. I can particularly recommend Len Lichtenfeld's feed. This has been a very contentious issue - as most of you know, Avastin was provisionally approved for these patients, then pulled when more trial data came in showing no benefit. Roche/Genentech's team is now appealing that decision, and the questions are:

1. Should Avastin be approved for metastatic breast cancer patients? The answer to this one is "depends on the evidence for it". So. . .

2. Is there enough evidence to decide one way or another? Both the FDA and Roche seem to think that there is. The problem's that they come to opposite conclusions. So. . .

3. What's the risk/benefit ratio for Avastin in these patients? Now the serious arguing starts. Avastin is not without its serious side effects - but metastatic breast cancer is a terrible disease. The initial reports were promising - but none of the larger follow-up trials have really confirmed those results. Genentech is proposing still another confirmatory trial, with the drug to stay approved during that period, but the FDA seems to be arguing that leaving the drug approved for this indication will hurt more people than it helps. There you have it.

And all of this is being done against a backdrop of emotional cancer patient testimony. The problem with that is summed up by one of the most fervent advocates, Patricia Howard, who told the FDA "I’m not just a statistic; it is in your hands to ensure that I don’t become one."

She is wrong. It pains me to say this, but she's wrong. If we're ever going to get anywhere with cancer (or any other disease), we're going to need all the statistics we can get our hands on, and no amount of passionate testimony should be allowed to move one number in them. I've had family members with cancer; I've seen good friends and plenty of good people die from cancer. But cancer cells do not care about how strong your feelings are. The growth factor receptors, the checkpoint kinases, the apoptosis regulators, the metabolic enzymes and cell adhesion proteins: they don't give a damn. They have no damn to give. We have to fight them on those terms, on that battlefield, because that's the only one that matters and the only one where they can be defeated.

As it stands, I agree with the FDA's position: I don't think that Avastin has been shown to offer enough benefit. The 2008 provisional approval was already arguable - the agency went against its own advisory committee just to do that much - and the subsequent data have made it even less tenable. If we're going to have provisional approvals, then they have to be able to be taken back. And if we're going to evaluate drugs by their risks versus their benefits, then Avastin - for this indication, in these patients - doesn't (to my eyes) seem to make the cut.

If, on the other hand, you disagree with the provisional approval process, fine. Propose something more useful. If you disagree with the risk/benefit analysis in this case, then you should bring some new numbers or some new arguments (which is what Genentech is trying to do right now, as I write this, and I hope that they don't slip over the line while doing it). If you disagree with the whole idea of risk/benefit analysis, then. . .well, you'd better have something more useful to offer. And you'd better be sure that it doesn't end with the decisions going to whoever is the most passionate and tearful in making their case. That won't end well.

One more side issue: you'll note that I've done this whole blog post without talking about the price of Avastin at all. That's because I don't think that the price is the issue at all here. This is not a health-care-rationing issue, no matter how much some people would like for it to be. Roche gets to charge what they think Avastin can bring - they and Genentech have put the time, effort, and money into the drug. But for metastatic breast cancer, as I said here, Avastin doesn't seem like a good idea even if it were free.

Comments (63) + TrackBacks (0) | Category: Cancer | Regulatory Affairs


COMMENTS

1. RickW on June 29, 2011 9:26 AM writes...

Great post, I agree 100%. Politics and emotional pleas have to be kept out of these decisions as much as possible.

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2. Anonymous Academic on June 29, 2011 10:05 AM writes...

That's because I don't think that the price is the issue at all here

Of course price is the issue. There is nothing preventing doctors from prescribing Avastin for breast cancer off-label right now, and continuing to do so regardless of what the FDA rules. The reason FDA approval is so contentious is that it essentially determines whether insurance companies will cover its (massive) cost. Without approval, it will be effectively be beyond the reach of most patients. This isn't (and shouldn't be) a factor in the FDA's deliberation, but as far as the patient advocates are concerned, it's overwhelmingly important. (Genentech/Roche, of course, have mostly different motives, but they're much less emotionally charged.)

I don't disagree with your overall point, but I think you're much too idealistic about the process. I'm sure we can expect to see many more controversies like this in the future, especially if and when the government becomes more involved in providing (or guaranteeing) health insurance.

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3. Hap on June 29, 2011 10:33 AM writes...

Won't the cost of a drug and its FDA approval for an indication always be an issue as long as health insurance (either private or government-run/-facilitated) is the primary payer for health care? There's no reason to figure that the costs for drugs won't go up, so for most individuals, whether someone else will pay is the issue. While you could sue an insurance company to try to get them to pay (and not the government), the FDA approval (or lack) will probably trump anything else in court, so the FDA approval would be the key in any case. Is that right?

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4. InfMP on June 29, 2011 10:46 AM writes...

Even employees in the Roche empire would have to listen to that post.

tight.

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5. qetzal on June 29, 2011 11:15 AM writes...

@Anonymous Academic,

I agree with Derek - price is not the issue. The question is whether Avastin provides any net clinical benefit to women with metastatic breast cancer. If the answer is "No," then there's no reason for docs to prescribe it for that indication, off-label or not. The fact that it would become too expensive would be irrelevant.

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6. Anonymous Academic on June 29, 2011 11:28 AM writes...

@qetzal: The question is whether Avastin provides any net clinical benefit to women with metastatic breast cancer. If the answer is "No," then there's no reason for docs to prescribe it for that indication, off-label or not.

Again, I agree in principle, but desperately ill people will pursue any treatment they think may help them, medical science be damned, and they believe (wrongly, in my opinion) that insurers should cover these treatments. If Avastin cost only a few hundred dollars a month, we wouldn't be seeing protestors outside the FDA.

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7. Brent Michael Krupp on June 29, 2011 11:51 AM writes...

Reminds me of the huge controversy about paying for autologous bone marrow transplants for breast cancer back in the 90s. The patient advocates (and patients) were just damn sure it was a miracle and that insurance companies hated them. Turned out it killed women. Oops.

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8. Chuck Pelto on June 29, 2011 11:53 AM writes...

TO: All
RE: Heh

....desperately ill people will pursue any treatment they think may help them....If Avastin cost only a few hundred dollars a month, we wouldn't be seeing protestors outside the FDA. -- Anonymous Academic

They should look into pawpaw. I've seen the dried stems and leaves of this tree kill an aggressive squamous carcinoma on the forearm within a month.

Regards,

Chuck(le)
[God made the Earth and everything therein for Man. Our problem has been trying to figure out how to use it all....properly.]

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9. MTK on June 29, 2011 11:54 AM writes...

AA,

I'm going to have to side with DL and qetzal on this one. The issue is efficacy and safety for this indication.

While I understand what you're saying regarding reimbursement, should not the protestors be outside the insurance companies then, and not the FDA?

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10. pete on June 29, 2011 11:55 AM writes...

If FDA rules "against Avastin" so to speak, I can't help but wonder how big the ripple effect may be for other targeted drug candidates in oncology indications. The pressure to effectively pre-screen for patients most likely to benefit would grow ever greater, I think.

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11. mark abrams on June 29, 2011 12:18 PM writes...

patients should decide what treatment they desire. their doctors should provide advice on the possible treatments and report the results (maintaining a database of disease/treatment/results would be a worthwhile public service) . Of course none of this is possible unless the patients pay (directly or through private, defined benefits insurance) for their own treatment.

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12. Owen on June 29, 2011 12:21 PM writes...

What about the Personalized Medicine story: does that apply here? Is there any evidence that Avastin works well in subgroups (with different tumor characteristics; or who metabolize things differently; etc) so that, if a proper biomarker or other diagnostic tool can be fashioned, the drug would be targeted at only/mostly the "right" tumors in only/mostly the "right" patients?

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13. victor on June 29, 2011 12:24 PM writes...

price is not the issue.

the issue is that avastin only works on a subpopulation of those treated. if roche could tease out and document the biological qualities of this responsive subgroup, they would have no issue with FDA approval.

because there is no evidence that roche has taken this track,they may find avastin pulled from the marked.

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14. FrankD on June 29, 2011 12:33 PM writes...

I guess I don't understand about the side effect issue. Just to oversimplify, if there are 1000 pts in a study, and 200 get cured by the treatment, and 200 get a fatal side effect, then is the argument that there is no positive risk/benefit? Except, this is a fatal disease. So, the 200 who got the fatal side effect were going to die anyway. So, wouldn't the net effect be a 20% positive effect? What am I missing?

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15. Carl Pham on June 29, 2011 12:33 PM writes...

I'm sorry, you want the FDA to disapprove the drug because...it might not on average do enough good?

Did someone die and make you (or the clowns in Washington) God? Who the hell are either of you, or any of you, to make the final decision what drug a desperate patient might reasonably try, on a clinician's hunch and a prayer?

I would have no objection if the FDA pulled its approval because the approval was fraudulent, or its side-effects were completely unknown and quite possibly fatal, or it was as utterly useless as Laetrile and crystals. But to pull it merely because on average it doesn't seem to do noticeably better is arrogant and obnoxious, and regardless of the law (always an ass), I can see zero moral justification for it.

Furthermore, speaking of statistics, we already know well that response to chemotherapy is quite individualized, which means knowing the benefit for the average patient when pondering an individual therapeutic choice is about as useful as knowing the average US home price while house-shopping in your particular neighborhood, with your particular resources and needs -- that is, not very. This should be taken into account by people who appreciate the power and limitations of statistics.

Which is to say, I disagree with you. I don't think we just need more statistics, more averaging over clearly important genetic and environmental variables. We do indeed need more "anecdotes," in the sense of individual stories -- but "anecdotes" that consists of measureable and repeatable chains of cause and effect. We need to know that this individual factor leads to that individual outcome, every time, so that we can finally tailor the therapy to the individual disease from which the patient is suffering.

I doubt anyone thinks there will ever be "a" cure for metastatic breast cancer. But there may very well be 100,000 different cures for 100,000 different types of patient and varieties of the disease.

Permalink to Comment

16. teapartydoc on June 29, 2011 12:35 PM writes...

Another good reason to privatize the FDA. We get official word on the research-level worthiness of a drug. And we are then free to take our risks with it if we so choose.

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17. Carl Pham on June 29, 2011 12:40 PM writes...

And, yes, pulling approval does mean denying the drug to most people, as soon as the insurers stop paying for it.

Sure, ha ha, it can be used "off label" by rich patients, or patients who had the foresight to not fork out $10,000 a year in health insurance premiums, Medicare/Medicaid taxes, et cetera, for the past 20 years, and save their healthcare dollars personally instead, so that they could now pay cash for the drug they want.

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18. CR on June 29, 2011 12:41 PM writes...

@15, Carl Pham...
"Did someone die and make you (or the clowns in Washington) God? Who the hell are either of you, or any of you, to make the final decision what drug a desperate patient might reasonably try, on a clinician's hunch and a prayer?"

Then why have an approval process at all? Why not just put everything out there (regardless of efficacy data) and let physicians go out on a hunch to see what may work? Company A gets drug X approved, let's not reveal what it works on (or what it doesn't work on) and just let doctor's "hunch and pray" it will be good for disease Y.

Yeah, that's how medicine should be practiced.

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19. FrankD on June 29, 2011 12:55 PM writes...

I guess I don't understand about the side effect issue. Just to oversimplify, if there are 1000 pts in a study, and 200 get cured by the treatment, and 200 get a fatal side effect, then is the argument that there is no positive risk/benefit? Except, this is a fatal disease. So, the 200 who got the fatal side effect were going to die anyway. So, wouldn't the net effect be a 20% positive effect? What am I missing?

Permalink to Comment

20. Matthew Herper on June 29, 2011 1:00 PM writes...

@14 The problem is nobody is being cured. All that's been proven is that Avastin increases the amount of time until a tumor gets bigger -- and the magnitude of that benefit is smaller in the newer studies. So the question is how you balance that against the known side effects.

Also, whether this gets paid for is up to CMS, not FDA. Lots of drugs are reimbursed for unapproved uses.

Permalink to Comment

21. watcher on June 29, 2011 1:08 PM writes...

Of course cost and pricing is involved in these decisions, particularly when we all are at the mercy of our insurance companies, the government, some bigger consorteum to negotiate the actual payment (and out of pocket co-pays) for our personal medications.

Yesterday, you put up a question as to when public opinion about drug companies began to deteriorate. The answer is not specifically the direct to consumer advertising, even though that activity came about as part of the greater problem. The major contributor was drug costs & the increasingly common image of industry greed. The vastly increasing charges for new and year to year price increases for existing drugs are seen & felt by the public every day. New drug pricing is very often set at what the market will tolerate (which includes insurance & / or government payers). For example, typically, the cost of a course of treatment for a new oral drug for oncology taken at home will take into account the premium which current IV, in-clinic / hospital treatments carry, trying to get close to the same total cost of treatment. other words, it's the going rate for cancer therapy, so we should continue to get the same amount even though it can be taken at home without other assistence.

What a self-serving system! Provides great profits to the company, but often hardship to the patient and/or even the payer.

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22. Rich on June 29, 2011 1:43 PM writes...

Following this drug in breast cancer and seeing patients in forums clearly benefiting from it, sometimes just by itself, my impression is there are subgroups more likely to benefit and there are issues with needing to continue it beyond progression to maintain the benefit. In terms of predicting benefit, there are methods that could revolutionize the use of ALL chemotherapies. It's called chemosensitvity testing. A GP can adequately treat a bladder infection if a sample (urine) is sent for sensitivity to specific agents. In chemosensitivity testing, a sample of the tumor is subjected to various chemos to help choose the treatment most likely to work..just like antibiotics in a UTI. Both disease processes have selection for resistance and drug toxicity issues. It would be irresponsible to avail a UTI patient of an antibiotic sensitivity test. picking an antibiotic based on randomized trials amongst various patients would be irresponsible. Why do we accept that approach in cancer when in many cases there is a way to get a tumor sample and check it for sensitivity before subjecting a patient to therapies that may only offer them toxicity. In a breast cancer patient, the initial surgery excision would typically offer enough sample to test. Imagine the long term remission rate if choice of therapy was guided by individualized testing instead of statistical averages? Imagine the money saved by avoiding pointless cycles of ineffective therapies that might only damage the patient and create mutations leading to more resistant disease? We can spend millions trying to model the seemingly endless variables of cancer based on incomplete theory..or use an approach that recognizes the individuality of cancer patients is at least equal to that of UTI patients. And yes..there is a lab pursuing the same style of testing for anti-angiogenic treatments such as Avastin. Plenty of other approved chemos have horrible side effects and we continue to wrecklessly administer them in blind hope of benefit. For most I have seen, Avastin is a walk in the park in comparison to Taxotere, Taxol and others. That said, I have a feeling improper use of Avastin may be costly and potentially do more harm than good. But the same can be said for therapies that are mainstays. The problems are bigger than Avastin..it is..no pun intended..systemic.

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23. Hap on June 29, 2011 1:48 PM writes...

17: Great...if you're paying. If somebody else is paying (insurance or gov't), then someone has to make choices about what to pay for. Money paid to reimburse for drugs that don't work or don't work well is money that can't be used for something else that might work better. If the FDA approves everything so that payers have to compensate for everything, whether it works or not, then health insurance degrades to "Take while you can, because soon there'll be none to take", which of course ends up killing lots of those who can no longer get care at all after the money and resources run out.

So to follow "pay for everything" also makes life-and-death decisions (by removing resources that could be used to help others) - it just makes them badly. That'll work well.

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24. pete on June 29, 2011 1:50 PM writes...

following Len Lichtenfeld's Tweets...
Based on current picture, it looks like Avastin has hit a brick wall at FDA for metastatic breast cancer. Significant committee concerns about the health risk of putting pts. on Avastin. That, as well as the underwhelming data for mean clinical benefit.

Permalink to Comment

25. Rich on June 29, 2011 2:01 PM writes...

I have to add...chemosensitivity testing offers the opportunity to try therapies not normally considered for a given cancer. An example would be a breast cancer drug for a prostate cancer patient..prostate cancer considered to have very limited options. Those who work with this technique demonstrate instances where out of the box testing on the samples revealed vulnerability to low toxicity therapies that simply wouldn't be considered by an oncologist blindly picking from the standard menu of options. So it can not only limit exposure to harmful and ineffective therapies, it can open the door to more options likely to help.

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26. TOSG on June 29, 2011 2:05 PM writes...

Rich: Sure, but the behavior of tumor cells in a petri dish is going to be very different from the behavior of those cells in their native environment. For instance, it would be difficult to recapitulate the activity of Avastin in an environment lacking vascularization and a blood supply. It's a nice idea, but I'm not so sure it'd be useful in practice.

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27. Spiny Norman on June 29, 2011 2:29 PM writes...

"Following this drug in breast cancer and seeing patients in forums clearly benefiting from it, sometimes just by itself..."

The problem is that without measurable clinical outputs and strong controls you and they haven't the slightest idea how much clinical benefit there is, or what additional risks are present. No. Idea. None. You can't know.

Once more, with(out) feeling: THE PLURAL OF "ANECDOTE" IS NOT "DATA."

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28. Rich on June 29, 2011 2:45 PM writes...

TOSG,
3D tumorspheres..not single cells in petri dish. See Rational Therapeutics and Weisenthal labs.

Spiny,
If you can do it "without feeling", you be the one to withdraw a drug that has clearly worked.
I was just trying to suggest that overall landscape is riddled with inadequacies. Drugs are approved or rejected based on flawed trials with limited benefit on a regular basis. This one is really getting a workover due to its cost.

I would rather increase the number of tools in the arsenal and work towards identifying benefit in individual not average cases.

If we made oncology decisions more informed and individualized, the savings from avoiding drugs not likely to work, could offset the occassions when an expensive drug like Avastin would benefit.

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29. Greg Pawelski on June 29, 2011 3:12 PM writes...

The petri dish scenario is really old hat. Twenty years old hat. Newer technologies have been debunking that adage for years, whether in vitro tests are of any use, as the in vivo response to a drug may very well be different in the body than in the petri dish.

Any number of oncologists' training and practice does not include studying and understanding the cancer cell and its relationship to the rest of the body's cellular mechanics and communication. Cellular biology is a very complex and fascinating body of knowledge which a number of private clinical scientists appreciate and understand. They are constantly looking for ways to reverse that cell physiology and in a non-toxic way as possible.

Continued development of better cancer drugs is driven by increased understanding of cancer cell biology. Perhaps if some oncologists did rotations like medical students do, they would develop more of an understanding and appreciation of what it is they are doing. Most oncologists still mistakenly refer to two distinct 'old' types of assays: Salmon/Von Hoff human tumor stem cell assay and clonogenic assay, which hasn't been used in private labs in over twenty years. This is the assay ASCO talks about in their infamous 2004 tech assessment. Over twenty year old material that had been discredited twenty years ago.

With the limitations of old cell culture assay technology, which only used two dimensions (2D) from which information is gathered, the newer cell culture technology works with three dimensions (3D), which is able to provide data on the behavior of cells towards cancer drugs when they are in a complex relationship which resembles or mimics their situation inside the human body.

The protocol that Rational Therapeutics and Weisenthal Cancer Group uses takes 'fresh' patient tumor cells and floats them in newer 3D cell suspensions. Even researchers at Johns Hopkins and Washington University in St. Louis have found out our body is 3D, not 2D in form, undoubtedly, this novel step better replicates that of the human body. Traditionally, in-vitro (in lab) cell-lines have been studied in 2 dimensions (2D) which has inherent limitations in applicability to real life 3D in-vivo (in body) states. Recently, other researchers have pointed to the limitations of 2D cell line study and chemotherapy to more correctly reflect the human body.

The bottom line is the cell-based functional profiling assay is able to predict the patient's response to treatment. It does this by measuring the net effect of all processes within the cancer, acting with and against each other in real-time because it tests fresh (live) cells, in their natural state (native environment), actually exposed to drugs and drug combinations of interest, before they are administered to the patient.

Labs that perform chemo sensitivity without a surgical specimen usually proliferate (grow) cancer cells from a smaller sample obtained by a blood or needle biopsy and subject those cells to chemo. Because they test on subcultured cells (as opposed to 'fresh' tumor cultures) and test the cells in monolayers (as opposed to three dimensional cell clusters), the cells grown in the lab will not behave the same way as the actual cancer cells do in your body's own environment.

All of the work in the past twenty years in the cell culture field has been carried out largely on three dimensional clusters of cells (not monolayers). Work is done exclusively with three dimensional, floating, tumor spheroids.

Permalink to Comment

30. Greg Pawelski on June 29, 2011 3:34 PM writes...

Genetech is proposing still another confirmatory trial. Fine. But without drug appoval yet. Their researchers have been looking for tests to help predict how patients will respond to Avastin. Perhaps they should use the cell-based functional profiling platform (AngioRx Assay) to identify a potential targeted population of cancer patients that it thinks will benefit from Avastin, and then conduct a randomized clinical trial among this group.

However, unlike some genetic assays that look whether an individual has a particular mutation or amplification, and therefore tests for theoretical candidates for a particular targeted drug, the functional profiling technique may find Avastin not synergistic (cooperative) and finds some other VEGF-targeted (or multiple VEGF-targeted) drug may work better in an individual cancer patient and then put that individual into the clinical trial. I can understand they may not want some other drug tested on their dime.

There are a number of new classes of drugs that target VEGF, at the protein level (Avastin), at the tyrosine kinase level (Nexavar, Sutent) and at the intracellular metabolic pathway mTOR (Afinitor, Torisel). However, responses to any individual mechanism occurs in the miniority of patients. It is unclear why some patients repond to these interventions while others fail. In cell function analysis, it has found unexpectedly good response to conventional cytotoxic drugs following a failure to respond to these targeted agents.

This reinforces the need for cancer therapies to be individualized. It remines us that it is the good outcome of the patient not the therapy applied that constitute successful therapy. There is really nothing wrong with Avastin. It is a wonderful drug that incorporates the brilliant insights originally articulated by Judah Folkman. There are not perfect drugs. There are simply drugs that work for certain patients. But that is not what pharmaceutical companys like to hear. They like to produce drugs that apply to a broad base of patients. To make the most out of a drug, not just some subsets of patients.

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31. Anonymous on June 29, 2011 3:39 PM writes...

Humankind cannot stand very much reality.

(T S Eliot)

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32. DonM on June 29, 2011 4:03 PM writes...

How about this paradigm. Let the patient, aided by their doctor(s) decide. They have the most to win and lose.

Who thinks that it is part of Genetech's business model to sell drugs that poison more people than it helps? Who thinks bureaucrats care have a balanced view regarding patients who die with no medicine, and patients who die from side effects from an approved drug. Of course the FDA disapproves, they are never embarassed by drugs they do not approve.

The federal government has no enumerated powers to regulate medicine. The entire agency is unconstitutional. They should all be fired.

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33. watcher on June 29, 2011 4:03 PM writes...

The right side of this vote by the panel today.

http://news.yahoo.com/roche-seeks-more-time-avastin-breast-cancer-143822138.html

Example of why much of the public gets frustrated by drug companies....Roche wants to keep the current conditional approval in-place while they continue to conduct more studies to see if the compound is worth using for breast cancer. My goodness. Let's keep putting the gas tank in back of the rear axel as in the PINTO and let GM sell the car while more studies are done to further prove that the design kills people.

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34. DonM on June 29, 2011 4:12 PM writes...

The results of experiments, assays, or clinical trials could be provided to indpendent private third parties, (like the Council of Rabbis for Kosher foods or Underwriter's Laboratories for appliances).

That way information would be funded by the developer, and would come out without the government bureaucrat's desperate interest in not being embarrassed a la Thalidomide.

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35. Garrett on June 29, 2011 4:14 PM writes...

qetzal,
"The question is whether Avastin provides any net clinical benefit to women with metastatic breast cancer." To be pedantic, I think the question is 'whether any drug will provide any net clinical benefit' in advance of the treatment being given. Of course, no result is guaranteed so we look at statistical averages. If statistically a benefit would be found, then we might look at cost.

Carl Pham,
"Who the hell are either of you, or any of you, to make the final decision what drug a desperate patient might reasonably try, on a clinician's hunch and a prayer?"

Err, well, the delegates of the people paying for it, actually. However, there's another word in there which needs to be looked at. That's "reasonably". The problem is that the only advanced knowledge we have about this drug is that on average it makes people worse off. Not everybody, but you can't know that ahead of time. That's the problem. Discover that it only works in people with brown eyes and suddenly the equation tips the other way (and likely, so does the FDA approval). However, until then, giving this drug to a patient is on average going to make them worse isn't reasonable in the slightest - it actually strikes me as medical malpractice.

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36. DensityDuck on June 29, 2011 5:26 PM writes...

If you ever wondered why the pharmaceutical industry is just spending all its money on boner pills and happy juice...

this is why.

Permalink to Comment

37. Ray on June 29, 2011 5:26 PM writes...

I haven't read all of these comments in detail, but there is one overriding point that seems to be missed here. You seem to think that all women, or all patients, are essentially interchangeable, which enables you to make choices on the basis of statistics that are not clear-cut.

The fact is that the same medicine can have totally different and opposite effects in different patients. I have seen this repeatedly over the years. Works for some, not for others.

For those the medicine works for, it will probably continue to work. Having found out empirically, for one specific woman, that the drug works, it is not humane or reasonable to deprive her of it, whatever the mechanism. This is an experiment that can only be carried out one patient at a time. It cannot be decided by statistics.

It is morally wrong to interpose a group of uninterested bureaucrats between a willing adult buyer, who has the only direct experience of the drug's effects on her, and a willing seller. The motivation seems to me to be that the insurance companies want to use the government to provide them the excuse to decline coverage, to improve their bottom line.

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38. DerekF on June 29, 2011 6:08 PM writes...

@Ray (37):

"It is morally wrong to interpose a group of uninterested bureaucrats between a willing adult buyer, who has the only direct experience of the drug's effects on her, and a willing seller. The motivation seems to me to be that the insurance companies want to use the government to provide them the excuse to decline coverage, to improve their bottom line."

(1) The problem is that the "willing adult buyer" has no experience of the drug unless/until it is prescribed and the effect seen. Thus what you are in essence arguing for is that the approval process for drugs be abolished - anyone can get whatever they can persuade their doctor to prescribe and their insurer (which means all of us, pretty much, since insurance money comes from our premiums not out of thin air) to pay for. I don't see anything particularly morally compelling about that, especially if, on average, the risk/benefit ratio disfavors the treatment.
(2) Roche/Genentech's motivation seems to me to be to use the government to provide them with an excuse to convince insurance companies (again, us) to pay for a treatment that, on the average again, has an unfavorable risk/benefit ratio. The insurance companies have no standing in the FDA decision: they just live with it - the parties here are Roche/Genentech on the one hand, and the FDA experts interpreting Roche/Genentech's own data on the other.

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39. CatCube on June 29, 2011 6:35 PM writes...

@Ray (37):

"It is morally wrong to interpose a group of uninterested bureaucrats between a willing adult buyer, who has the only direct experience of the drug's effects on her, and a willing seller."

But does the fact that the patient thinks that the drug does any good matter? There are people who will scream from the rooftops that thimerosol gave their kid autism, and others will swear up and down that a treatment diluted down to one molecule cured what ailed them. People can convince themselves of anything. Without data to back it up, Avastin for breast cancer is no different than homeopathy.

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40. MTK on June 29, 2011 6:39 PM writes...

@32

"The federal government has no enumerated powers to regulate medicine. The entire agency is unconstitutional."

The commerce clause would say otherwise. As would Justice Scalia. See Gonzalez v. Raich

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41. ussmidway on June 29, 2011 6:44 PM writes...

Rich, Greg, Owen, et. al. -

I have been tracking advances in tumor profiling and personalized medicine for many years, and you all make interesting points.

I would just add the following -- all IMHO:

> Ex-vivo cell culture assays have come a long way, but even the best 3D systems will be a crude proxy for the dynamic in-vivo setting, and to reach broad, clinical acceptance they may need to be coupled with another kind of assay that characterizes the tumor more holistically; not just focused on chemo-sensitivity. The 2 data points combined could be a powerful input to decision-making.

> At their best, ex-vivo assays still replicate the old empiric therapy model that has become less common in oncology, but remains the norm in other fields, like rheumatology and neurology. Basically this approach is based on trial & error: throw many potentially useful drugs against the cell cultures, and see what hurts them the most.

These assays are NOT based on a detailed understanding of activated cell-signaling pathways and the molecular processes driving malignancy. Therefore, as we move into the world where the "inner secrets" of these diseases are revealed, we will eventually look back on ex-vivo technology as an interim step on a long journey. As the assays mature, it is likely that certain applications may retain significant clinical utility for specific questions well into the future -- especially in an adjunctive role that can be correlated with other disease metrics, but I doubt that any are destined to be the end-state solution for the most critical issues in medicine.

> Avastin was developed and approved during the pre-dawn twilight of the personalized medicine era. There is little question that if it were being approved for the first time in 2011, the Phase 3 data would be broken down by relevant biomarker stratification and the label would include the pre-requisite of a positive test of some kind to clarify the subset(s) of breast cancer patients who are statistically more, or less likely to achieve a net medical benefit. This would hypothetically render the current FDA argument moot. Given the stakes, I think GNE may be at risk of having a 3rd party develop a well-validated classifier assay for Avastin in breast and other cancers, in which case they would lose some strategic control of the product franchise. FDA owns the labels and can make changes based on input from any qualified party, so if GNE dawdled on this opportunity and they get upstaged by somebody else with an approved assay for one of their top drugs, it will not look good.

At the time it was launched, GNE was still reading from the old script that drove marketing of new drugs so as to maximize their utilization, regardless of whether there was an actual benefit at the level of the individual patient. As a result, pricing models and projections for future revenues were built to these "launch specs" and once these are set, it is politically very difficult to make any changes that are not positive.

This all may seem to strange to those who would cite the Herceptin experience as evidence GNE was already doing this. But Herceptin would never have been approved without the Her-2neu assay, Avastin was able to hit sufficiently impressive response numbers in unselected populations in the other tumors (CRC & NSCLC) such that an up-front assay was not necessary for FDA approval. Furthermore, despite some early hopes that VEGF assays alone would be predictive, it now seems clear that any effective assay for Avastin will need to interrogate multiple signaling pathways -- one marker will not solve this riddle. As it turns out, even the established Her-2neu assays for Herceptin are now being re-engineered and could ultimately evolve along the same lines, with assays that combine multiple biomarkers.

Roche/Genentech appears to be a far more realistic organization today as it relates to understanding the implications of incorporating individual disease biology into drug development and commercialization. We will see how this plays out for over time -- have they really shifted from the maximization approach to one more aligned with optimization? Time will tell...

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42. Rich on June 29, 2011 7:06 PM writes...

Unfortunately, "the old empiric therapy model" is in actuality the mainstay of cancer overall. Outside of trials, in breast cancer there are only a few markers to guide the guessing. And again, positive sensitivity testing can bring to bare tools that supposed cancer knowledge scratches from the list. As you say, the assays for characteristics and potentially active pathways/receptors are will continue evolving. Meanwhile, the people doing the 3D functional profiling don't have the support to do tri-phase clinical trials. But they are getting positive, tangible results for the patients lucky enough to learn of the option.

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43. Matthew Herper on June 29, 2011 8:20 PM writes...

@36: Actually, the pharmaceuticals industry is pretty much done with boner pills and is quickly abandoning happy juice. It's putting lots of money into cancer drugs, though, and Avastin is one of the industry's best sellers. This will not discourage further investment in cancer medicine.

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44. Greg Pawelski on June 29, 2011 8:33 PM writes...

Ray

Absolutely. The same medicine can have totally different and opposite effects in different patients. One breast cancer patient's life saving therapy may be another's pulmonary embolism without clinical benefit. There are no perfect drugs. There are simply drugs that work for certain patients.

Until such time as cancer patients are selected for therapies predicated upon their own unique biology, we will confront one Avastin after another. The solution to this problem is to investigate the VEGF targeting agents in each individual patient’s tissue culture, alone and in combination with other drugs, to gauge the likelihood that vascular targeting will favorably influence each patient’s "individual" outcome.

Avastin had "accelerated" approval based on the condition that additional trials would be conducted after the approval. Those additional trials showed no significant benefit. The FDA evaluates new cancer medicines for "accelerated" approval by rapidly approving promising drugs for advanced diseases that are poorly treated with existing medicines. Accelerated approval was granted on Avastin based on a surrogate endpoint study rather than the gold standard of overall survival, bona fide clinical efficacy, or quality of life improvement.

I agree that most of the excitement about this drug has a lot more to do with a cooredinated marketing and business development effort by Roche than the native merit of the drug itsel.

ussmidway

The 3D analysis is very dynamic in the in-vivo setting. In the body, cells interact with and are supported by other living cells, both malignant and non-malignant cells. That is why cell-death functional profiling assays study cancer cells in small clusters, or microspheroids (microclusters).

Analysis of these microspheroids provides a snapshot of cancer's behavior within the human body and provides a more accurate representation of how cancer cells are likely to respond to treatment in the clinic. It "will" be indicative of what will happen in the human body.

There is no manipulation of isolated cancer cells to make them grow, which was an important point of distinction with earlier cell-growth assays.

Real-life cancers grow as a complex organism that includes both malignant and non-malignant components. It may include fibrous tissue, mesothelial cells, fibroblasts, endothelial cells, etc.

In order to exhibit its most characteristic behavior patterns, a cancer cell needs to be surrounded by a colony of other cells, both normal and malignant.

Human tumors represent micro-ecosystems composed of transformed cells, stroma, fibroblasts, vascular elements, extra-cellular protein matrices and inflammatory elements.

The behavior of human cancers and their reponse to therapy reflect the complex interplay between humoral, vascular, adhesion and cytokine-mediated events acting in concert.

Tumors are very complex organisms. Ignoring this complexity, most studies of human cancer in culture have focused upon individual tumor cells that have been removed from their complex microenvironoment.

Cells are routinely broken up by mechanical and enzymatic means, which alters their subsequent behavior. Some previous methods of assays limited their analysis only to isolated tumor cells and failed to incorporate the crucial contribution of non-tumorous elements to the cancer phenomenon.

When allowed to grow in vitro, living cancer cells develop into these tiny micro-spheroid clusters that form a complex biosystem in which each malignant cell reacts upon its fellow colonists in subtle but important ways.

Each of these microspheres contains all the complex elements of tumor biosytems that are found in the human body and which can impact clinical reponse.

In short, it is a complex and thorough analysis. Not many medical oncologists understand it.

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45. cliffintokyo on June 29, 2011 10:00 PM writes...

I agree with everything in your post, and most of the comments too.
Your hypothetical "if it were free" postulate skirts an interesting point for an external observer of US culture.
My outsider's view is that the US is totally preoccupied with $$$$$$$$$$$$$$$$$$$$$$$$$$$, to the exclusion of any objective, scientific decision making.
This observation leads to the conjecture that an unfortunate, less-than-wealthy cancer patient in the US would be quite likely to chose Avastin over ANY other cancer drug if it was offered free.
If Roche and their advocates truely believe Avastin is a good drug for treating metastatic breast cancer, would they care to test this hypothesis?

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46. Drug Wonk on June 29, 2011 10:18 PM writes...

@DerekF

Who are these "uninterested bureaucrats"? FDA is staffed by physicians and scientists. You think they don't want to see effective drugs? You've got some nerve - of course they do. What about the unanimous advisory committee? Oncologists who treat these patients every day. They, along with the FDA, don't want a drug that hurts more people than it helps. What is that you want?

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47. Rich on June 29, 2011 11:46 PM writes...

"What is that you want?"

An admission that they largely guess based on questionable study methodology and far from comprehensive genomic and molecular theory. Using buzzwords like individualized therapy while shooting from the hip. Admit it. Change it.

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48. Terry Liu on June 30, 2011 1:54 AM writes...

Indeed, Aastin is a bio medical very good at curing eye disease, which can replace the photo dynamic therapy method to treat the DME, a common eye disease popular in elder ppl in west countries. There are lots of reports that drs in western countries use it to treat DME in practice, even though, the treatment is not approved by FDA. However, the company refused to have a clinical trail for this new treatment for eye disease due to the relatively less profit.

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49. cliffintokyo on June 30, 2011 1:58 AM writes...

@ 46 & 47
Thanks for the perspective (?!) comments from the Avastin Advocate Delegation.
If Roche did not believe that Avastin is a good drug, they would not have appealed the FDA decision to yank the mbc indication?
But their own clinical data from several trials do not provide a basis for a reappraisal?
So what is the basis for the appeal?
Perhaps they are hoping to *appeal* to the *instincts* of disinterested bureau-cats. IMHO, there was a chance that they might have *succeeded* without watchdogs such as "In the Pipeline" keeping an eye open.

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50. Rich on June 30, 2011 2:36 AM writes...

Sorry Cliff..
Not part of any organized "delegation". Simply have a mom with metastatic breast cancer and I have seen the russian roulette treatment paradigm play itself out for many a patient. if you truly read my posts, you are either on board for this terrible journey or in a place where you have the luxury to bury your head. Toodles.

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51. Cliff on June 30, 2011 3:03 AM writes...

Hi Rich,
No personal insults intended.
So many people (including myself) have lost a family member to cancer.
There are few illusions around this blog about the
terrible journey, as you accurately describe it, that is involved.
Wish your mom the very best of luck,
Cliff

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52. Greg Pawelski on June 30, 2011 11:20 AM writes...

Terry Liu

Avastin for radiation-induced necrosis? When brain tumors are treated with radiation therapy, there is always a risk of radiation-induced necrosis of healthy brain tissue. Insidious and potentially fatal, radiation necrosis of the brain may develop months or even years after irradiation. Recent studies at M. D. Anderson have shown that Avastin may be able to stop radiation necrosis of the brain and allow some of the damage to be reversed. The findings suggest that radiation necrosis of the brain can be successfully managed and perhaps even prevented with Avastin or similar drugs.

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53. Josh on June 30, 2011 11:48 AM writes...

Derek- One of your best (of many superb) commentaries. You nailed it. Avastin simply doesn't work in this case. You might as well try Rolaids. Even the FDA got this one right. I don't think cost is a factor here either (although that will rear its ugly head soon enough). Ironic though, that the EU approved it the same day. Go figure.

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54. Otis on June 30, 2011 12:23 PM writes...

#1. I did hear the end of the Avastin argument on MSNBC. It put the sensationalist host in a very hard spot to "sell the controversy" on the 24hr news: (roughly) The people this drug killed are not here to give their emotional testimony. This drug harms people, and does no good.

Also: Bravo CatTube!

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55. DerekF on June 30, 2011 1:31 PM writes...

@DrugWonk (46):

"Uninterested bureaucrats" was Ray (36)'s term not mine. The paragraph was in quotes for a reason.
See also CatCube (39), who did the same thing.
I'm not advocating for anything other than good science and sensible regulatory practice, certainly not for Avastin keeping it's approval for breast cancer, I was disagreeing with Ray.

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56. Terry Liu on June 30, 2011 2:18 PM writes...

Greg Pawelski


There are several classes of drugs that are being employed in the management of DME, including corticosteroids (triamcinolone acetonide) and the anti-VEGF drugs (pegaptanib, bevacizumab, and ranibizumab), that researchers hope may improve upon laser therapy, including possibly restoring vision loss. It should be emphasized, however, that none of these drugs is currently approved by the US Food and Drug Administration (FDA) for the treatment of DME.

Very recently in shanghai , there is an interesting application of Avastin as drug for treatment of DME, however, this time , there are some bad news for Drs, the cause reason is not the drug itself or the treatment itself. A couple of patients suffer from inflammation after the shot of the Avastin into the eyes. After a investigation of this incident, the authority of china, SFDA made the conclusion, it is the Avastin being contaminated by the un correct storage conditions, (these drs divided one of the standard dose of Avastin , the drug is not approved in china yet, and some of them are smuggled illegally from drs in hongkong.) into 10 portions for the purpose of treatment of 10 patients with DME. Despite of the effectiveness of the treatment worldwide, this method is only accepted in china for DME treatment under the table. Soon the SFDA claimed that the treatment is illegal and the drugs are faked drugs. This is the story of Avastin, to me I am interested to file a NADA application to SFDA and challenge the patent in china as a biomedicine drug for treatment of cancers. Anyone have any ideas about the defect of the patent regarding this issue?

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57. qetzal on June 30, 2011 3:06 PM writes...

@45 cliffintokyo

My outsider's view is that the US is totally preoccupied with $$$$$$$$$$$$$$$$$$$$$$$$$$$, to the exclusion of any objective, scientific decision making.

I have no idea how you can say this, considering that the FDA decision is all about objectively demonstrated risks and benefits, and specifically excludes any consideration of cost.

If Roche and their advocates truely believe Avastin is a good drug for treating metastatic breast cancer, would they care to test this hypothesis?

It's very likely that they already have. It's pretty standard that the experimental drug is provided free to participants in a trial. And, unfortunately for Roche, the results appear to be very underwhelming.

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58. DCRogers on June 30, 2011 5:03 PM writes...

"Medicare to Continue to Cover Avastin Regardless of What FDA Decides"

http://abcnews.go.com/Health/BreastCancerCenter/medicare-cover-avastin-fda-decision/story?id=13970046

If I were a scientist on the FDA panel, I'd feel a little less than useless, and used.

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59. CatCube on June 30, 2011 7:30 PM writes...

@DerekF (55):

I was responding to Ray as well, hence the "@Ray (36)" at the top of my post.

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60. Anonymous on June 30, 2011 7:57 PM writes...

@57
Thanks for your objective appraisal of my outburst (its HOT here).
I was hedging my bets; my comment about money fixation concerned the US in general.
I was hoping that FDA would demonstrate that they are maintaining their scientific standards in the face of such emotional blackmail.
My faith in the US FDA was just restored.

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61. cliffintokyo on June 30, 2011 7:59 PM writes...

@57
Thanks for your objective appraisal of my outburst (its HOT here).
I was hedging my bets; my comment about money fixation concerned the US in general.
I was hoping that FDA would demonstrate that they are maintaining their scientific standards in the face of such emotional blackmail.
My faith in the US FDA was just restored.

(Sorry about the unattributed first try)


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62. DerekF on July 2, 2011 12:09 PM writes...

@CatCube (59)

Sorry if my comment at 55 wasn't clear - I meant to say something like "CatCube also quoted Ray (note quotation marks) and also disagreed with him", which I think is what you were doing, but I was too taken aback by DrugWonk's rant to be careful enough in my writing.
Probably should have just said "'Uninterested bureaucrats' is Ray's term - talk to him." or just, as the saying goes, saved my breath to cool my porridge.

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63. mariage on September 15, 2011 12:20 PM writes...

Thank you for talking about "Avastin At the FDA Today: Passion Should Lose. In the Pipeline:".

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